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Second-generation antipsychotics and seizures - a systematic review and meta-analysis of serious adverse events in
Leonie Reichelt1, Orestis Efthimiou2, Stefan Leucht3
1Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Klinikum rechts der Isar, Munich 81675, Germany; Institute for Radiology, Krankenhaus Landshut -Achdorf, Landshut, Germany.
Abstract:
Seizures are suspected to be side effects of antipsychotics. To examine a possible causal relationship, we compared the risk of seizures on second-generation antipsychotics to the risk on placebo in randomized controlled clinical trials (RCTs) across diagnostic groups. The primary outcome was any seizure reported as International Conference on Harmonisation-Good Clinical Practice (ICH-GCP)-defined serious adverse event (SAEs). The risk ratio (RR) with antipsychotics versus placebo was synthesized in a pairwise common effects Mantel-Haenszel meta-analysis. For 314 of 597 idenitified placebo-controlled RCTs information about all SAEs could be retrieved from publications, original investigators, pharmaceutical companies and the European Medical Agency. In those, 37 seizures occurred in 42,600 participants on antipsychotics (0.09%) and 28 in 25,042 participants on placebo (0.11%). The meta-analytic results (RR 0,68; 95% Confidence Interval 0.41-1.12) indicated a reduced risk on antipsychotics with a confidence interval including no difference (i.e. RR=1). Neither in sensitivity analyses (excluding events in the safety-follow-up of trials or first-generation antipsychotics; using odds ratios) nor in subgroup analyses (on specific antipsychotics, drug combinations, diagnostic categories, age groups, and study duration) there was evidence for an increased risk on antipsychotics, except for some weak indications of an increased risk on antipsychotics in older and/or demented participants (RRs 1.11 and 1.48, respectively, but with 95% CIs of 0.35-3.49 and 0.41-5.26 including no difference and subgroup tests with p=0.54 and p=0.66 not indicating differences between age groups or diagnostic categories). Consequently, there are no indications that second-generation antipsychotics cause seizures in middle-aged adults and children in most diagnostic groups; rather our results provide some weak evidence for a protective effect. However, there was no data on SAEs available for clozapine, for which observational studies provide the strongest associations with increased seizure rates, and for older and/or demented patients a small additional risk on antipsychotics cannot be excluded.
Insights
Second-generation antipsychotics do not appear to increase seizure risk in most patients. While generally safe, a small risk may exist for older or demented individuals, but more data is needed for clozapine.
Area of Science:
- Neuroscience
- Clinical Pharmacology
Background:
- Antipsychotic medications are widely used, but concerns persist regarding their potential to induce seizures.
- Understanding the seizure risk associated with second-generation antipsychotics (SGAs) is crucial for patient safety.
Approach:
- A meta-analysis synthesized data from 314 placebo-controlled randomized clinical trials (RCTs) involving 42,600 participants on SGAs and 25,042 on placebo.
- Serious adverse events (SAEs), including seizures, were analyzed using a common effects Mantel-Haenszel meta-analysis to calculate risk ratios (RRs).
- Sensitivity and subgroup analyses explored potential variations in risk across different patient groups and study designs.
Key Points:
- The overall meta-analysis indicated a reduced risk of seizures with SGAs compared to placebo (RR 0.68), though the confidence interval included no difference.
- No increased seizure risk was found in most diagnostic groups, age categories, or study durations.
- Weak indications of increased risk were observed in older and/or demented participants, but confidence intervals were wide and subgroup tests were not significant.
Conclusions:
- Current evidence does not support the hypothesis that SGAs cause seizures in the general patient population, including children and middle-aged adults.
- A small, potential increase in seizure risk for older and/or demented patients cannot be entirely ruled out.
- Data on clozapine, an SGA associated with higher seizure rates in observational studies, was not available for this analysis.
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